JP2013079220A - Transdermal absorption type patch containing rotigotine - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a transdermal absorption type patch containing rotigotine that is capable of inhibiting production of rotigotine decomposition products.SOLUTION: In the transdermal absorption type patch composed of a base material, a drug-containing layer, and a release liner, the drug-containing layer contains a rubber pressure-sensitive adhesive, a quantity of rotigotine effective for treatment or prevention, and a production inhibitor for rotigotine decomposition products.

Description

  The present invention relates to a transdermal patch comprising a support, a drug-containing layer containing rotigotine and a production inhibitor of rotigotine degradation products, and a release liner.

  Rotigotine is a D3 / D2 / D1 dopamine receptor agonist, and is a drug having an excellent effect on Parkinson's disease, rest legs syndrome (RLS) and the like. So far, preparations containing rotigotine as an active ingredient have been developed. For example, Neupro (registered trademark), which is a transdermal patch containing rotigotine, is commercially available in Europe and other regions.

  In addition to the above, for example, Patent Document 1 discloses a rotigotine-containing transdermal patch containing an acrylate or silicone polymer adhesive as a base. Patent Document 2 and Patent Document 3 disclose rotigotine-containing transdermal patches containing a polyvinylpyrrolidone as a solubilizer and an acrylate-based and / or silicone-based polymer adhesive as a base. Patent Document 3 also contains rotigotine containing an acrylate-based and / or silicone-based polymer adhesive as a base and an antioxidant such as tocopherol and its ester derivatives, ascorbyl palmitate, sodium bisulfite, and the like. A transdermal patch is disclosed.

  However, adhesives other than acrylate-based or silicone-based polymers as a base, for example, a rotigotine-containing transdermal absorption patch containing a rubber-based adhesive as a base is not disclosed, and the rubber-based adhesive is not disclosed. The advantageous effects such as the effectiveness and transdermal absorbability of the formulated rotigotine-containing transdermal patch have not been disclosed at all.

Special table 2002-509878 gazette Special table 2004-536054 gazette Japanese translation of PCT publication 2010-532390

  An object of the present invention is to provide a novel transdermal absorption patch containing rotigotine, specifically, a transdermal absorption patch containing rotigotine in which a rubber-based adhesive is blended in a base. Is to provide.

  In order to solve the above-mentioned problems, the present inventors have conducted extensive research, and as a result, in the rotigotine-containing transdermal patch containing a rubber-based adhesive in the base, a decomposition product of rotigotine is produced. confirmed. Accordingly, the present inventors have developed a rotigotine-containing transdermal absorption patch that suppresses the degradation product of the rotigotine. Specifically, in a transdermal patch comprising a support, a drug-containing layer containing rotigotine and a rubber-based adhesive, and a release liner, the drug-containing layer is further combined with a production inhibitor of rotigotine degradation products The present invention was completed by using the transdermal absorption patch.

  The inventors of the present invention have confirmed for the first time that the above-described degradation product of rotigotine is produced when a rotigotine-containing transdermal patch containing a rubber-based adhesive is stored for a certain period of time. And it discovered that it could suppress by containing a predetermined substance in a composition as a production | generation inhibitor of the decomposition product of this rotigotine.

  Here, the degradation product of rotigotine referred to in the present invention is unknown in detail, but when rotigotine-containing transdermal absorption patch was stored for a certain period of time, rotigotine changed in the drug-containing layer, derived from rotigotine It is a substance. The degradation product of rotigotine can be confirmed when the rotigotine-containing transdermal absorption patch is analyzed under the analysis conditions described in the following test examples. In particular, in the analysis, the generation of a decomposition product (hereinafter referred to as “decomposition product A”) whose retention time is detected at about 18 minutes is remarkable. The present invention suppresses the generation of decomposition product A in a rotigotine-containing transdermal absorption patch, and further reduces the total amount of decomposition products by adding a generation inhibitor of decomposition products of rotigotine. This is the first time that

  The rotigotine-containing transdermal absorption patch of the present invention is capable of suppressing the production of rotigotine degradation products in a drug-containing layer containing a rubber-based adhesive. It can be stored for a long time, and the pharmacological effect of rotigotine can be used effectively and for a long time.

  The production inhibitor of a decomposition product of rotigotine according to the present invention (hereinafter simply referred to as “production inhibitor”) is a compound that can suppress or delay the production of a decomposition product of rotigotine. . For example, when the production inhibitor is blended with a rotigotine-containing transdermal absorption patch, the degradation product A is compared with a blend with a general antioxidant or a blend with no production inhibitor. This has the effect of reducing the generation amount of or generating delay.

In addition, the amount of rotigotine degradation product A of the present invention can be obtained under the analysis conditions described in the test examples described below in consideration of a decrease in rotigotine content due to the degradation of rotigotine, and a decrease in pharmacological effect and quality. In addition, the value calculated by the following formula (1) from each peak area is preferably 1.1% or less, more preferably 0.7% or less.

A / X (1)

A: Peak area of decomposition product A
X: Sum of peak areas of rotigotine, degradation product A and other degradation products

In the transdermal patch of the present invention, rotigotine or a salt thereof can be used as an active ingredient. The salt of rotigotine is not particularly limited and can be an inorganic salt or an organic salt as long as it is a pharmaceutically acceptable salt. Examples thereof include rotigotine hydrochloride. In the present invention, it is preferable to use a free form of rotigotine.

  The content of rotigotine or a salt thereof in the transdermal absorption patch of the present invention is 1 to 40%, preferably 5 to 30%, more preferably 7 to 20% with respect to the mass of the entire drug-containing layer. When the content is less than 1%, a sufficient pharmacological effect of rotigotine is not exhibited, and when it exceeds 40%, an increase in the pharmacological effect of rotigotine correlated with the dose is not observed, which is not preferable.

  The transdermal patch of the present invention is characterized by blending a rubber adhesive as a base. The rubber-based pressure-sensitive adhesive is cheaper than other non-water-based pressure-sensitive adhesives, for example, pressure-sensitive adhesives such as an acrylic polymer and a silicone-based polymer, and controls production costs, physical properties, quality, and the like. That is, it is preferable in terms of easy formulation design.

  The compounding amount of the rubber component of the rubber-based pressure-sensitive adhesive is 0.1 to 98% with respect to the total mass of the drug-containing layer of the transdermal absorption patch of the present invention, and 0.1 to 70%. Preferably, 0.1 to 50% is more preferable. When the blending amount of the rubber component is less than 0.1%, the physical properties of the patch such as anchoring properties are degraded, and when it exceeds 98%, the adhesive strength to the skin is good when the patch is applied to the human body. Is not preferable.

  The rubber component of the rubber-based pressure-sensitive adhesive of the present invention is, for example, styrene / isoprene / styrene block copolymer (SIS) [for example, JSR Kraton Elastomer Co., Ltd .; Kraton D-KX401CS (trade name), Kraton D-1161JP (Trade name), Shell Chemical Co., Ltd .; Califlex TR-1107 (trade name), TR-1111 (trade name), TR-1112 (trade name), TR-1117 (trade name), Nippon Synthetic Rubber Co., Ltd. ); JSR5000 (brand name), JSR-5002 (brand name), SR5100 (brand name), Nippon Zeon Co., Ltd .; QUINT 3530 (brand name), 3570C (brand name), 3421 (brand name), etc.], Styrene / butadiene / styrene block copolymer (SBS) [for example, Shell Chemical Co., Ltd .; Califlex TR-1101, etc.] Styrene-butadiene rubber (SBR), polyisobutylene (PIB) [for example, Shin Nippon Petrochemical Co., Ltd .; Tetrax 3T (trade name), BASF Japan Ltd .; Opanol B150 (trade name), etc.], polybutene (PB) ) [For example, Nippon Petrochemical Co., Ltd .; HV300F (trade name), etc.], butyl rubber (IIR), natural rubber (NR) and isopropylene rubber (IR) [for example, Nippon Zeon Co., Ltd .; nipol IR2200 (product) Name) etc.].

As the production inhibitor of the transdermal patch of the present invention, sulfites such as sodium bisulfite, sodium sulfite, sodium pyrosulfite, potassium pyrosulfite, and mercaptobenzimidazole can be used alone or in combination. Among these, sodium hydrogen sulfite, sodium pyrosulfite, and mercaptobenzimidazole are preferable.

  The blending amount of sulfite and / or mercaptobenzimidazole in the transdermal absorption patch of the present invention is 0.005 to 2.0% with respect to the total mass of the drug-containing layer, and 0.01 to 2.0. % Is preferred. If the blending amount is less than 0.005%, a sufficient decomposition product of rotigotine, particularly degradation product A, cannot be obtained, and even if it exceeds 2.0%, production suppression correlated with the blending amount. The improvement of the effect is not recognized, which is not preferable.

  The production inhibitor of a transdermal absorption patch of the present invention is further characterized by having an effect of suppressing rotigotine crystal formation over time during storage of the patch. For example, when the production inhibitor is added to a rotigotine-containing percutaneous absorption type patch, the drug-containing layer is compared with a preparation containing a general antioxidant or a preparation containing no production inhibitor. That has the effect of suppressing or delaying the formation of crystals of rotigotine or a salt thereof over time (ie, a rotigotine crystal formation inhibitor).

  The rotigotine-containing transdermal patch of the present invention contains additional components such as a plasticizer, a crosslinking agent, a colorant, an ultraviolet absorber, a tackifier, an antioxidant, and a transdermal absorption enhancer as necessary. You may mix | blend.

  Plasticizers include petroleum-based oils such as paraffinic process oil, naphthenic process oil, and aromatic process oil, and liquid fatty acid esters such as isopropyl myristate, hexyl laurate, diethyl sebacate, diisopropyl sebacate, and isopropyl linoleate. , Olive oil, camellia oil, castor oil, tall oil, peanut oil and other vegetable oils, glycerin, chlorobutanol, vinyl acetate resin, dimethylpolysiloxane / silicon dioxide mixture, D-sorbitol, medium chain fatty acid triglycerides, triacetin, pyrrolidones Phytosterol, propylene glycol, polyethylene glycol, polysorbate 80 (registered trademark), glyceryl monostearate and the like.

  Examples of the crosslinking agent include amino resins, phenol resins, epoxy resins, alkyd resins, thermosetting resins such as unsaturated polyesters, isocyanate compounds, organic crosslinking agents, and inorganic crosslinking agents such as metals or metal compounds.

  Colorants include indigo carmine, yellow iron oxide, yellow iron sesquioxide, carbon black, caramel, photosensitive element 201, Kumazasa extract, black iron oxide, ketket, zinc oxide, titanium oxide, iron sesquioxide, amaranth, hydroxide Sodium, talc, copper chlorophyllin sodium, green leaf extract powder, D-borneol, octyldodecyl myristate, methyl rosaniline chloride, methylene blue, manganese ammonium phosphate, rose oil and the like.

  Examples of UV absorbers include amino acid compounds such as urocanic acid, benzophenone compounds such as 2,4-dihydroxybenzophenone and 2-hydroxy-4-n-octoxybenzophenone, and cinnamic acids such as sinoxate and p-methoxycinnamic acid diethanolamine. Derivatives, cyanoacrylate derivatives such as 2-ethylhexyl-2-cyano-3,3′-diphenylacrylate, p-aminobenzoic acid derivatives such as ethyl p-aminobenzoate and propyl p-aminobenzoate, anthranilate menthyl ester, etc. Anthranilic acid derivatives, salicylic acid derivatives such as phenyl salicylate and p-octylphenyl salicylate, and coumarin derivatives such as 7-ethylamino-4-methylcoumarin and 7,8-dihydroxycoumarin.

  Examples of tackifiers include rosin, rosin glycerin ester, hydrogenated rosin, rosin derivatives such as hydrogenated rosin glycerin ester, alicyclic saturated hydrocarbon resin, alicyclic hydrocarbon resin, terpene resin, aliphatic saturated carbonization. Hydrogen resin, aliphatic hydrocarbon resin, maleic resin, carnauba wax, carmellose sodium, xanthan gum, chitosan, glycerin, magnesium aluminum silicate, light anhydrous silicic acid, benzyl acetate, talc, hydroxyethyl cellulose, hydroxypropyl cellulose, hypromellose, poly Examples include acrylic acid, sodium polyacrylate, partially neutralized polyacrylic acid, and polyvinyl alcohol.

  Antioxidants include hindered phenol compounds [eg, 3,5-ditertiarybutyl-4-hydroxytoluene (BHT), 3- (3,5-ditertiarybutyl-4-hydroxyphenyl) Propionic acid octadecyl ester, tetrakis [methylene-3- (3,5-ditertiarybutyl-4-hydroxyphenyl) propionate] methane, tris 3,5-ditertiarybutyl-4-hydroxybenzyl) isocyanurate, 4,4'-butylidenebis (3-methyl-6-tert-butylphenol), triethylene glycol bis [3- (3-tertiary butyl-4-hydroxy-5-methylphenyl) propionate], pentaerythris Lityl tetrakis [3- (3,5-di-tert-butyl-4-hydroxyphenyl) propionate] <Irganox 1010 (Product Name)>, 3,9-bis {2- [3- (3-tertiarybutyl-4-hydroxy-5-methylphenyl) propionyloxy] -1,1-dimethylethyl} -2,4 8,10-tetraoxaspiro [5,5] undecane, etc.], ascorbic acid and its ester derivatives, sodium edetate, citric acid, potassium diisocyanurate, soybean lecithin, thymol, tocopherol and its ester derivatives, 1,3 -Butylene glycol, benzotriazole, monothioglycerin and the like.

  Percutaneous absorption enhancers include alkanolamines such as diisopropanolamine and triisopropanolamine, fatty acids such as lauric acid, oleic acid, isopropyl myristate, octyldodecyl myristate, glycerin oleic acid monoester, hexadecyl isostearate or esters thereof. , Oleyl alcohol, propylene glycol, alcohols such as polyethylene glycol monooleate or esters thereof or ethers thereof, sorbitan esters or ethers such as sorbitan monolaurate, sorbitan monooleate, polyoxyethylene nonylphenyl ether, poly Phenol ethers such as oxyethylene octylphenyl ether, castor oil or hydrogenated castor oil, oleoyl sarco , Ionic surfactants such as lauryl dimethylaminoacetic acid betaine, sodium lauryl sulfate, nonionic surfactants such as polyoxyethylene oleyl ether, polyoxyethylene lauryl ether, dimethyl lauryl amine oxide, dimethyl sulfoxide, decyl Alkyl methyl sulfoxides such as methyl sulfoxide, pyrrolidones, azacycloalkanes such as 1-dodecylazacycloheptan-2-one, 1-geranylazacycloheptan-2-one, menthol, camphor, limonene, etc. Examples include terpenes.

  As the support in the transdermal patch of the present invention, a drug-impermeable, stretchable or non-stretchable support is used. Examples of the support include synthetic resin films or sheets such as polyethylene, polypropylene, polybutadiene, ethylene vinyl acetate copolymer, polyvinyl chloride, polyester (polyethylene terephthalate, etc.), nylon, polyurethane, etc., or laminates thereof, porous materials Examples include body, foam, paper, woven fabric and non-woven fabric.

  As the release liner in the transdermal patch of the present invention, a drug-impermeable release liner is used. Examples of the release liner include a film made of a polymer material such as polyethylene, polypropylene, and polyester, a film in which aluminum is vapor-deposited on a film, and a film in which silicone oil is coated on paper. . Among them, a polyester film is preferable from the viewpoints of no penetration of active ingredients, processability and low cost, and a polyethylene terephthalate (PET) film is particularly preferable. Further, examples of the release liner include a laminate film obtained by bonding a plurality of materials.

  The method for producing the transdermal patch of the present invention is not particularly limited, and can be produced according to a known production method. As the production method, for example, an active ingredient and an adhesive are dissolved in an organic solvent such as ethyl acetate, hexane, toluene or a mixed solvent thereof, and the dissolved product is spread on a release liner or a support, and the dissolved product is obtained. After evaporating the solvent and forming a drug-containing layer, a method for obtaining a transdermal absorption patch by laminating a support or a release liner, and heating and melting active ingredients and adhesives, etc. Examples include a method of obtaining a transdermal absorption patch by spreading on a release liner or a support to form a drug-containing layer and then bonding the support or the release liner.

  Hereinafter, the present invention will be described more specifically with reference to examples. The present invention is not limited to these examples, and various modifications can be made without departing from the technical idea of the present invention.

Example 1
According to the mixing ratio shown in Table 1, styrene-isoprene-styrene block copolymer [Clayton Elastomer Co., Ltd .; Kraton D-KX401CS (trade name)], hydrogenated rosin glycerin ester [Arakawa Chemical Industries, Ltd .; ester gum KE-311 (trade name)] and liquid paraffin [Hicoal M352 (trade name)] are stirred and mixed in toluene. A rotigotine solution prepared by mixing an aqueous solution of sodium pyrosulfite with a toluene solution of rotigotine was added to the mixture and mixed by stirring to obtain a uniform dissolved product. The dissolved product is spread on a release film (PET film subjected to silicone treatment, Fujimori Kogyo Co., Ltd.) using a doctor knife coating machine so that the thickness after evaporation of the solvent is 100 μm. After spreading, the solvent was distilled off to form a drug-containing layer, and then the support was bonded and cut into a desired size to obtain the transdermal absorption patch of Example 1.

Example 2
According to the compounding ratio shown in Table 1, the transdermal patch of Example 2 was obtained by the same production method as Example 1 except that a methanol solution of mercaptobenzimidazole was used instead of the sodium pyrosulfite aqueous solution. It was.

Comparative Example 1
According to the blending ratio shown in Table 1, a transdermal absorption type patch of Comparative Example 1 was obtained by the same production method as Example 1, except that no sodium pyrosulfite aqueous solution was blended.

Comparative Example 2
According to the blending ratio shown in Table 1, the percutaneous absorption type of Comparative Example 2 was prepared in the same manner as in Example 1 except that a methanol solution of L-ascorbyl palmitate was used instead of the sodium pyrosulfite aqueous solution. A patch was obtained.

Comparative Example 3
According to the blending ratio shown in Table 1, a transdermal patch of Comparative Example 3 was obtained by the same production method as Example 1 except that a toluene solution of tocopherol was used instead of the sodium pyrosulfite aqueous solution.

Comparative Example 4
According to the blending ratio shown in Table 1, a transdermal patch of Comparative Example 4 was obtained by the same production method as Example 1 except that a toluene solution of dibutylhydroxytoluene was used instead of the sodium pyrosulfite aqueous solution. It was.

Comparative Example 5
According to the blending ratio shown in Table 1, the percutaneous absorption type of Comparative Example 5 was produced in the same manner as in Example 1 except that a toluene solution of Irganox 1010 (trade name) was used instead of the sodium pyrosulfite aqueous solution. A patch was obtained.

Comparative Example 6
According to the mixing ratio shown in Table 1, styrene-isoprene-styrene block copolymer [Clayton Elastomer Co., Ltd .; Kraton D-KX401CS (trade name)], hydrogenated rosin glycerin ester [Arakawa Chemical Industries, Ltd .; ester gum KE-311 (trade name)] and liquid paraffin [Hicol M352 (trade name)] after stirring and mixing in toluene, a toluene solution of rotigotine in a sodium pyrosulfite aqueous solution and a methanol solution of L-ascorbic acid palmitate ester Then, a rotigotine solution mixed with a toluene solution of tocopherol was added and mixed by stirring to obtain a uniform dissolved product. Next, using a doctor knife coating machine, this dissolved product was spread on a release film so that the thickness after evaporation of the solvent was 100 μm, and the solvent was distilled off to form a drug-containing layer. The bodies were pasted together.

Test example 1
About each test substance of Examples 1-2 and Comparative Examples 1-6, the production amount of the degradation product A and other rotigotine degradation products was measured. The decomposition product A indicates a decomposition product whose retention time is detected at about 18 minutes when measured under the following analysis conditions.
Each test substance cut into 5 cm ² was packaged one by one with aluminum packaging material and stored at room temperature for 2 months.
After storage, peel off the release sheet of each test substance, 50
It took into the mL centrifugation sedimentation tube, tetrahydrofuran 5mL was added, and it shaked for 20 minutes, and dissolved the paste. To this solution, 5 mL of methanol / phosphoric acid (200: 1, v / v) was added and shaken for 20 minutes to completely coagulate and precipitate the adhesive base component. The supernatant was quantified by high performance liquid chromatography.
In the operation of high performance liquid chromatography, the column is XBridge ™ C18 (5 μm, 3.0 mm × 10 cm; manufactured by Nihon Waters Co., Ltd.), the detection wavelength is 270 nm, and the mobile phase is water / trifluoroacetic acid (5000: 1, v / v). ) (Mobile phase A), methanol for liquid chromatography (mobile phase B), and liquid transfer of the mobile phase were carried out by mixing mobile phase A and mobile phase B under arbitrary conditions and controlling the concentration gradient.
By this method, the amount of decomposition product A and the total amount of decomposition products of each test substance were measured. The results are shown in Table 2.

    In Comparative Examples 1 to 6, decomposition product A was produced in an amount of 1.19 to 1.47%. On the other hand, in Example 1, almost no decomposition product A and other decomposition products were produced, and in Example 2, 0.39% decomposition product A was produced. From this result, it was revealed that the amount of decomposition product A produced was remarkably reduced in the patch of the present invention containing sodium pyrosulfite and mercaptobenzimidazole as production inhibitors.

Example 3
According to the blending ratio shown in Table 3, styrene-isoprene-styrene block copolymer [Clayton Elastomer Co., Ltd .; Kraton D-KX401CS (trade name)], hydrogenated rosin glycerin ester [Arakawa Chemical Co., Ltd .; ester gum KE-311 (trade name)] and liquid paraffin [Hicoal M352 (trade name)] are stirred and mixed in toluene. A rotigotine solution prepared by mixing an aqueous solution of sodium pyrosulfite with a toluene solution of rotigotine was added to the mixture and mixed by stirring to obtain a uniform dissolved product. Next, this dissolved material is spread on a release film using a doctor knife coating machine so that the thickness after evaporation of the solvent is 50 μm. After spreading, the solvent was distilled off to form a drug-containing layer, and then the support was bonded and cut into a desired size to obtain the transdermal absorption patch of Example 3.

Example 4
The transdermal patch of Example 4 was obtained in the same manner as in Example 3 except that the amount of sodium pyrosulfite was changed according to the formulation ratio shown in Table 3.

Example 5
The transdermal patch of Example 5 was obtained in the same manner as in Example 3 except that the amount of sodium pyrosulfite was changed according to the mixing ratio shown in Table 3.

Example 6
The transdermal patch of Example 6 was obtained in the same manner as in Example 3, except that the amount of sodium pyrosulfite was changed according to the mixing ratio shown in Table 3.

Example 7
According to the blending ratio shown in Table 3, the transdermal patch of Example 7 was obtained by the same production method as Example 3 except that a methanol solution of mercaptobenzimidazole was used instead of the sodium pyrosulfite aqueous solution. It was.

Example 8
A transdermal absorption patch of Example 8 was obtained by the same production method as Example 7 except that the blending amount of mercaptobenzimidazole was changed according to the blending ratio shown in Table 3.

Example 9
The transdermal patch of Example 9 was obtained in the same manner as in Example 7 except that the blending amount of mercaptobenzimidazole was changed according to the blending ratio shown in Table 3.

Example 10
A transdermal absorption patch of Example 10 was obtained by the same production method as Example 7, except that the blending amount of mercaptobenzimidazole was changed according to the blending ratio shown in Table 3.

Example 11
According to the blending ratio shown in Table 3, the transdermal patch of Example 11 was obtained in the same manner as in Example 3, except that sodium hydrogen sulfite was used instead of sodium pyrosulfite.

Comparative Example 7
According to the blending ratio shown in Table 3, a transdermal patch of Comparative Example 7 was obtained by the same production method as in Example 3 except for the sodium pyrosulfite aqueous solution.

Test example 2
About each test substance of Examples 3-13 and Comparative Example 7, it preserve | saved for 30 days or 60 days at 40 degreeC, and it is the same measuring method as Test Example 1, and the production amount of decomposition product A and the total production of decomposition products The amount was measured. The results are shown in Table 4.

    The production amount of the decomposition product A of Comparative Example 7 containing no production inhibitor was 1.42% to 2.96%. On the other hand, the production amount of the decomposition product A of Examples 3 to 6 containing 0.01 to 0.15% sodium pyrosulfite as a production inhibitor was 0.00% to 0.69%. Similarly, the production amount of the decomposition product A of Examples 7 to 10 containing 0.01 to 0.6% of mercaptobenzimidazole was 0.00 to 0.57%. Furthermore, the production amount of the decomposition product A of Example 11 in which sodium bisulfite was also blended was 0.00%. From this result, it is clear that the production amount of the decomposition product A is remarkably reduced in the patch of the present invention containing 0.01% or more of sulfite such as sodium pyrosulfite or mercaptobenzimidazole as a production inhibitor. became.

Test example 3
For each test substance obtained in Examples 3, 6, 7, and 11 and Comparative Examples 1 to 6, the state of rotigotine crystal formation was evaluated. The evaluation method is as follows.
First, each test substance cut at an interval of 10 cm in width is packaged in petonium packaging material and stored at room temperature for 1 month or 4 months, and the crystal formation state of rotigotine after storage is observed visually and under a microscope. did. When observed, the case where there was no crystal formation of rotigotine was evaluated as ◯, and the case where there was crystal formation of rotigotine was evaluated as x. The results are summarized in Table 5.

    In Comparative Examples 1 to 6, crystal formation of rotigotine was observed after 4 months of storage. On the other hand, in Examples 3, 6, 7, and 11 in which sodium pyrosulfite, mercaptobenzimidazole or sodium bisulfite was blended as a production inhibitor, rotigotine crystal formation was not observed. From this result, in the patch of the present invention containing sulfite such as sodium pyrosulfite and mercaptobenzimidazole, there is almost no rotigotine crystal formation during patch storage, and rotigotine is contained in the paste layer in a dissolved state. It has been suggested.

Example 12
A transdermal patch of Example 12 was obtained in the same manner as in Example 11, except that the amount of sodium bisulfite was changed according to the mixing ratio shown in Table 6.

Example 13
A transdermal absorption patch of Example 13 was obtained in the same manner as in Example 3, except that the amount of sodium pyrosulfite was changed according to the mixing ratio shown in Table 6.

Example 14
According to the blending ratio shown in Table 6, styrene-butadiene-styrene block copolymer [Shell Chemical Co., Ltd .; Califlex TR-1107 (trade name)], hydrogenated rosin glycerin ester [Arakawa Chemical Industries, Ltd .; ester Gum KE-311 (trade name)] and liquid paraffin [Hicoal M352 (trade name)] are stirred and mixed in toluene. A rotigotine solution prepared by mixing an aqueous solution of sodium bisulfite with a toluene solution of rotigotine was added to the mixture and mixed by stirring to obtain a uniform dissolved product. The dissolved material is spread on a release film (PET film subjected to silicone treatment, Fujimori Kogyo Co., Ltd.) using a doctor knife coating machine so that the thickness after evaporation of the solvent is 50 μm. After spreading, the solvent was distilled off to form a drug-containing layer, and then the support was bonded and cut into a desired size to obtain the transdermal absorption patch of Example 14.

Example 15
According to the blending ratio shown in Table 6, a transdermal patch of Example 15 was obtained in the same manner as in Example 14, except that sodium pyrosulfite was used instead of sodium bisulfite.

Example 16
A transdermal absorption patch of Example 16 was obtained by the same production method as in Example 15 except that the blending amount of sodium pyrosulfite was changed according to the blending ratio shown in Table 6.

Example 17
A transdermal absorption patch of Example 17 was obtained in the same manner as in Example 14, except that the blending amount of sodium hydrogen sulfite was changed according to the blending ratio shown in Table 6.

Example 18
According to the mixing ratio shown in Table 6, polyisobutylene [Shin Nippon Petrochemical Co., Ltd .; Tetrax 3T (trade name)], hydrogenated rosin glycerin ester [Arakawa Chemical Industry Co., Ltd .; ester gum KE-311 (trade name) )] And liquid paraffin [Hicol M352 (trade name)] in toluene. A rotigotine solution prepared by mixing an aqueous solution of sodium pyrosulfite with a toluene solution of rotigotine was added to the mixture and mixed by stirring to obtain a uniform dissolved product. The dissolved material is spread on a release film (PET film subjected to silicone treatment, Fujimori Kogyo Co., Ltd.) using a doctor knife coating machine so that the thickness after evaporation of the solvent is 50 μm. After spreading, the solvent was distilled off to form a drug-containing layer, and then the support was bonded and cut into a desired size to obtain the transdermal absorption patch of Example 18.

Example 19
The transdermal patch of Example 19 was obtained in the same manner as in Example 18, except that the amount of sodium pyrosulfite was changed according to the formulation ratio shown in Table 6.

Example 20
A transdermal patch of Example 20 was obtained in the same manner as in Example 18, except that sodium bisulfite was used in place of sodium pyrosulfite according to the blending ratio shown in Table 6.

Example 21
According to the compounding ratio shown in Table 6, isopropylene rubber [Nippon Zeon Co., Ltd .; nipol
IR2200 (trade name)], hydrogenated rosin glycerin ester [Arakawa Chemical Co., Ltd .; ester gum KE-311 (trade name)] and liquid paraffin [Hicoal M352 (trade name)] are stirred and mixed in toluene. A rotigotine solution prepared by mixing an aqueous solution of sodium pyrosulfite with a toluene solution of rotigotine was added to the mixture and mixed by stirring to obtain a uniform dissolved product. The dissolved material is spread on a release film (PET film subjected to silicone treatment, Fujimori Kogyo Co., Ltd.) using a doctor knife coating machine so that the thickness after evaporation of the solvent is 50 μm. After spreading, the solvent was distilled off to form a drug-containing layer, and then the support was bonded and cut into a desired size to obtain the transdermal absorption patch of Example 21.

Example 22
The transdermal patch of Example 22 was obtained in the same manner as in Example 21, except that the amount of sodium pyrosulfite was changed according to the mixing ratio shown in Table 6.

Example 23
The transdermal patch of Example 23 was obtained in the same manner as in Example 21 except that the amount of sodium pyrosulfite was changed according to the formulation ratio shown in Table 6.

  The rotigotine-containing transdermal absorption patch of the present invention suppresses the formation of decomposition products of rotigotine or a salt thereof in the drug-containing layer. In addition, the rotigotine-containing transdermal absorption patch of the present invention easily suppresses crystal formation from a drug-containing layer of rotigotine or a salt thereof without using a special technique or the like. That is, according to the present invention, it is possible to provide a transdermal patch that can be stored for a long period of time and that can effectively and continuously utilize the pharmacological effect of rotigotine.

Claims (18)

In the rotigotine-containing transdermal absorption patch comprising a support, a drug-containing layer and a release liner, the drug-containing layer comprises:
(1) Rubber adhesive
(2) rotigotine or a salt thereof,
And (3) a production inhibitor of a decomposition product of rotigotine,
A transdermal absorption patch containing.   The rubber component of the rubber-based pressure-sensitive adhesive comprises a styrene-isoprene-styrene block copolymer, a styrene-butadiene-styrene block copolymer, a styrene-ethylene / butylene-styrene block copolymer, polyisobutylene and isopropylene rubber. The rotigotine-containing transdermal patch according to claim 1, wherein the patch is one or more selected from the group.   The rotigotine-containing transdermal absorption patch according to claim 1 or 2, wherein the production inhibitor of the decomposition product of rotigotine is at least one selected from mercaptobenzimidazole and sulfite.   The rotigotine-containing transdermal absorption patch according to any one of claims 1 to 3, wherein the sulfite is at least one selected from sodium bisulfite, sodium sulfite, sodium pyrosulfite and potassium pyrosulfite. .   The rotigotine-containing transdermal absorption patch according to any one of claims 1 to 3, wherein the sulfite is at least one selected from sodium bisulfite and sodium pyrosulfite.   The rotigotine-containing transdermal absorption patch according to any one of claims 1 to 5, wherein the content of the rotigotine or a salt thereof is 1 to 40 mass% with respect to the mass of the entire drug-containing layer.   The rotigotine-containing transdermal patch according to any one of claims 1 to 5, wherein the content of the rotigotine or a salt thereof is 5 to 30% by mass with respect to the mass of the entire drug-containing layer.   The rotigotine-containing transdermal patch according to any one of claims 1 to 5, wherein the content of the rotigotine or a salt thereof is 7 to 20% by mass with respect to the mass of the entire drug-containing layer.   The rotigotine-containing medium according to any one of claims 3 to 8, wherein the content of the sulfite and / or mercaptobenzimidazole is 0.005 to 2.0 mass% with respect to the mass of the entire drug-containing layer. Skin-absorbing patch.   The rotigotine-containing medium according to any one of claims 3 to 8, wherein the content of the sulfite and / or mercaptobenzimidazole is 0.01 to 2.0 mass% with respect to the mass of the entire drug-containing layer. Skin-absorbing patch.   The rotigotine-containing transdermal absorption patch according to any one of claims 1 to 10, wherein the amount of rotigotine degradation product A produced is 1.1 mass% or less.   The rotigotine-containing transdermal absorption patch according to any one of claims 1 to 10, wherein the amount of rotigotine degradation product A produced is 0.7 mass% or less.   The rotigotine-containing drug according to any one of claims 1 to 12, wherein the production inhibitor of the decomposition product of rotigotine suppresses crystal formation of rotigotine or a salt thereof from the drug-containing layer. Skin-absorbing patch.   The rotigotine-containing transdermal absorption patch according to any one of claims 1 to 13, which does not contain crystals of rotigotine or a salt thereof.   The rotigotine-containing transdermal absorption patch according to any one of claims 1 to 14, wherein the rotigotine-containing transdermal absorption patch further comprises a tackifier in the drug-containing layer.   The rotigotine-containing transdermal patch according to claim 15, wherein the tackifier is a hydrogenated rosin glycerin ester.   The rotigotine-containing transdermal absorption patch according to any one of claims 1 to 16, wherein the rotigotine-containing transdermal absorption patch further comprises a plasticizer in the drug-containing layer. The rotigotine-containing transdermal absorption patch according to claim 17, wherein the plasticizer is liquid paraffin.